1,6- diazabicyclo [3,2,1] octan-7-one derivatives and their use in the treatment of bacterial infections

ABSTRACT

Compounds of Formula (I), their preparation and use in preventing or treating bacterial infections are disclosed.

FIELD OF THE INVENTION

The invention relates to nitrogen containing compounds, use of thesecompounds as antibacterial agents, compositions comprising them andprocesses for their preparation.

BACKGROUND OF THE INVENTION

Emergence of bacterial resistance to known antibacterial agents isbecoming a major challenge in treating bacterial infections. One wayforward to treat bacterial infections, and especially those caused byresistant bacteria, is to develop newer antibacterial agents that canovercome the bacterial resistance. Coates et al. (Br. J. Pharmacol.2007; 152(8), 1147-1154.) have reviewed novel approaches to developingnew antibiotics. However, the development of new antibacterial agents isa challenging task. For example, Gwynn et al. (Annals of the New YorkAcademy of Sciences, 2010, 1213: 5-19) have reviewed the challenges inthe discovery of antibacterial agents.

Several antibacterial agents have been described in the prior art (forexample, see PCT International Application Nos. PCT/US2010/060923,PCT/EP2010/067647, PCT/US2010/052109, PCT/U52010/048109,PCT/GB2009/050609, PCT/EP2009/056178 and PCT/US2009/041200). However,there remains a need for potent antibacterial agents for preventingand/or treating bacterial infections, including those caused by bacteriathat are resistant to known antibacterial agents.

The inventors have surprisingly discovered nitrogen containing compoundswith antibacterial properties.

SUMMARY OF THE INVENTION

Accordingly there are provided nitrogen containing compounds, methodsfor preparation of these compounds, pharmaceutical compositionscomprising these compounds, and method for preventing or treatingbacterial infection in a subject using these compounds.

In one general aspect, there are provided compounds of Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof;wherein:

R₁ is:

-   -   (a) SO₃M,    -   (b) SO₂NH₂,    -   (c) PO₃M,    -   (d) CH₂COOM,    -   (e) CF₂COOM,    -   (f) CHFCOOM, or    -   (g) CF₃;

M is hydrogen or a cation;

R₂ is:

-   -   (a) hydrogen,    -   (b) (CH₂)_(n)—R₃, or    -   (c) COOR₃,

n is 0, 1 or 2;

R₃ is:

-   -   (a) hydrogen,    -   (b) C₁-C₆ alkyl optionally substituted with one or more        substituents independently selected from halogen, OR₅, CN,        COOR₅, CONR₆R₇, NR₆R₇, NR₅COR₈, NR₅CONR₆R₇, heterocyclyl,        heteroaryl, cycloalkyl or aryl,    -   (c) CN,    -   (d) NR₆R₇,    -   (e) CONR₆R₇,    -   (f) NHCONR₆R₇,    -   (g) aryl optionally substituted with one or more substituents        independently selected from C₁-C₆ alkyl, OR₅, NR₆R₇, halogen,        CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or        NHCONR₆R₇,    -   (h) heterocyclyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇,    -   (i) heteroaryl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇,    -   (j) cycloalkyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇,    -   (k) cycloalkyl substituted with C₁-C₆ alkyl wherein C₁-C₆ alkyl        is further substituted with one or more substituents        independently selected from OR₅, NR₆R₇, halogen, CN, or CONR₆R₇,        or    -   (l) OR₈;

R₄ is:

-   -   (a) hydrogen,    -   (b) C₁-C₆ alkyl optionally substituted with one or more        substituents independently selected from halogen, OR₅, CN,        COOR₅, CONR₆R₇, NR₆R₇, NR₅COR₈, heterocyclyl, heteroaryl,        cycloalkyl or aryl,    -   (c) aryl optionally substituted with one or more substituents        independently selected from C₁-C₆ alkyl, OR₅, NR₆R₇, halogen,        CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or        NHCONR₆R₇,    -   (d) heterocyclyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇,    -   (e) heteroaryl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇, or    -   (f) cycloalkyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇;

R₅ and R₈ are each independently:

-   -   (a) hydrogen, or    -   (b) C₁-C₆ alkyl optionally substituted with one or more        substituents independently selected from halogen, CN, CONR₆R₇,        NR₆R₇, heterocyclyl, heteroaryl, cycloalkyl or aryl;

R₆ and R₇ are each independently:

-   -   (a) hydrogen,    -   (b) C₁-C₆ alkyl optionally substituted with one or more        substituents independently selected from halogen, OR₅, CN,        COOR₅, CONR₅R₈, NR₅R₈, NR₅COR₈, heterocyclyl, heteroaryl,        cycloalkyl or aryl,    -   (c) aryl optionally substituted with one or more substituents        independently selected from C₁-C₆ alkyl, OR₅, NR₅R₈, halogen,        CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or        NHCONR₅R₈,    -   (d) heterocyclyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₅R₈,    -   (e) heteroaryl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₅R₈,    -   (f) cycloalkyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₅R₈, or    -   (g) R₆ and R₇ are joined together to form a four to seven member        ring.

In another general aspect, there are provided pharmaceuticalcompositions comprising a compound of Formula (I), or a stereoisomer ora pharmaceutically acceptable salt thereof.

In another general aspect, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of acompound of Formula (I) or a stereoisomer or a pharmaceuticallyacceptable salt thereof.

In another general aspect, there is provided a method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of a compound of Formula (I) or a stereoisomer or apharmaceutically acceptable salt thereof.

In another general aspect, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of apharmaceutical composition comprising a compound of Formula (I) or astereoisomer or a pharmaceutically acceptable salt thereof.

In yet another general aspect, there is provided a method for preventingor treating a bacterial infection in a subject, said infection beingcaused by bacteria producing one or more beta-lactamase enzymes, whereinthe method comprises administering to said subject a pharmaceuticallyeffective amount of a pharmaceutical composition comprising a compoundof Formula (I) or a stereoisomer or a pharmaceutically acceptable saltthereof.

In another general aspect, there are provided pharmaceuticalcompositions comprising: (a) a compound of Formula (I), or astereoisomer or a pharmaceutically acceptable salt thereof, and (b) atleast one beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof.

In another general aspect, there are provided pharmaceuticalcompositions comprising: (a) a compound of Formula (I), or astereoisomer or a pharmaceutically acceptable salt thereof, and (b) atleast one antibacterial agent or a pharmaceutically acceptablederivative thereof.

In another general aspect, there are provided pharmaceuticalcompositions comprising: (a) a compound of Formula (I), or astereoisomer or a pharmaceutically acceptable salt thereof, (b) at leastone beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof,and (c) at least one antibacterial agent or a pharmaceuticallyacceptable derivative thereof.

In another general aspect, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of apharmaceutical composition comprising: (a) a compound of Formula (I), ora stereoisomer or a pharmaceutically acceptable salt thereof, and (b) atleast one beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof.

In yet another general aspect, there is provided a method for preventingor treating a bacterial infection in a subject, said infection beingcaused by bacteria producing one or more beta-lactamase enzymes, whereinthe method comprises administering to said subject a pharmaceuticallyeffective amount of a pharmaceutical composition comprising: (a) acompound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, and (b) at least one beta-lactamase inhibitorselected from sulbactam, tazobactam, clavulanic acid, or apharmaceutically acceptable derivative thereof.

In another general aspect, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of apharmaceutical composition comprising: (a) a compound of Formula (I), ora stereoisomer or a pharmaceutically acceptable salt thereof, and (b) atleast one antibacterial agent or a pharmaceutically acceptablederivative thereof.

In yet another general aspect, there is provided a method for preventingor treating a bacterial infection in a subject, said infection beingcaused by bacteria producing one or more beta-lactamase enzymes, whereinthe method comprises administering to said subject a pharmaceuticallyeffective amount of a pharmaceutical composition comprising: (a) acompound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, and (b) at least one antibacterial agent or apharmaceutically acceptable derivative thereof.

In another general aspect, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of apharmaceutical composition comprising: (a) a compound of Formula (I), ora stereoisomer or a pharmaceutically acceptable salt thereof, (b) atleast one beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof,and (c) at least one antibacterial agent or a pharmaceuticallyacceptable derivative thereof.

In yet another general aspect, there is provided a method for preventingor treating a bacterial infection in a subject, said infection beingcaused by bacteria producing one or more beta-lactamase enzymes, whereinthe method comprises administering to said subject a pharmaceuticallyeffective amount of a pharmaceutical composition comprising: (a) acompound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, (b) at least one beta-lactamase inhibitorselected from sulbactam, tazobactam, clavulanic acid, or apharmaceutically acceptable derivative thereof, and (c) at least oneantibacterial agent or a pharmaceutically acceptable derivative thereof.

In another general aspect, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of:(a) a compound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, and (b) at least one beta-lactamase inhibitorselected from sulbactam, tazobactam, clavulanic acid, or apharmaceutically acceptable derivative thereof.

In yet another general aspect, there is provided a method for preventingor treating a bacterial infection in a subject, said infection beingcaused by bacteria producing one or more beta-lactamase enzymes, whereinthe method comprises administering to said subject a pharmaceuticallyeffective amount of: (a) a compound of Formula (I), or a stereoisomer ora pharmaceutically acceptable salt thereof, and (b) at least onebeta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanicacid, or a pharmaceutically acceptable derivative thereof.

In another general aspect, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of:(a) a compound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, and (b) at least one antibacterial agent or apharmaceutically acceptable derivative thereof.

In yet another general aspect, there is provided a method for preventingor treating a bacterial infection in a subject, said infection beingcaused by bacteria producing one or more beta-lactamase enzymes, whereinthe method comprises administering to said subject a pharmaceuticallyeffective amount of: (a) a compound of Formula (I), or a stereoisomer ora pharmaceutically acceptable salt thereof, and (b) at least oneantibacterial agent or a pharmaceutically acceptable derivative thereof.

In another general aspect, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of:(a) a compound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, (b) at least one beta-lactamase inhibitorselected from sulbactam, tazobactam, clavulanic acid, or apharmaceutically acceptable derivative thereof, and (c) at least oneantibacterial agent or a pharmaceutically acceptable derivative thereof.

In yet another general aspect, there is provided a method for preventingor treating a bacterial infection in a subject, said infection beingcaused by bacteria producing one or more beta-lactamase enzymes, whereinthe method comprises administering to said subject a pharmaceuticallyeffective amount of: (a) a compound of Formula (I), or a stereoisomer ora pharmaceutically acceptable salt thereof, (b) at least onebeta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanicacid, or a pharmaceutically acceptable derivative thereof, and (c) atleast one antibacterial agent or a pharmaceutically acceptablederivative thereof.

In another general aspect, there are provided methods for increasingantibacterial effectiveness of a antibacterial agent in a subject, saidmethod comprising co-administering said antibacterial agent or apharmaceutically acceptable derivative thereof with a pharmaceuticallyeffective amount of a compound of Formula (I) or a stereoisomer or apharmaceutically acceptable salt thereof.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects and advantages of theinvention will be apparent from the following description includingclaims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made to the exemplary embodiments, and specificlanguage will be used herein to describe the same. It shouldnevertheless be understood that no limitation of the scope of theinvention is thereby intended. Alterations and further modifications ofthe inventive features illustrated herein, and additional applicationsof the principles of the invention as illustrated herein, which wouldoccur to one skilled in the relevant art and having possession of thisdisclosure, are to be considered within the scope of the invention. Itmust be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. All references includingpatents, patent applications, and literature cited in the specificationare expressly incorporated herein by reference in their entirety.

The inventors have surprisingly discovered novel nitrogen containingcompounds having antibacterial properties.

The term “C₁-C₆ alkyl” as used herein refers to branched or unbranchedacyclic hydrocarbon radical with 1 to 6 carbon atoms. Typical,non-limiting examples of “C₁-C₆ alkyl” include methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl,n-hexyl and the like. The “C₁-C₆ alkyl” may be unsubstituted, orsubstituted with one or more substituents. Typical, non-limitingexamples of such substituents include halogen, alkoxy, CN, COOH, CONH₂,OH, —NH₂, —NHCOCH₃, cycloalkyl, heterocyclyl, heteroaryl, aryl and thelike.

The term “cycloalkyl” as used herein refers to three to seven membercyclic hydrocarbon radicals. The cycloalkyl group optionallyincorporates one or more double or triple bonds, or a combination ofdouble bonds and triple bonds, but which is not aromatic. Typical,non-limiting examples of cycloalkyl groups include cyclopropane,cyclobutane, cyclopentane, cyclohexane, and cycloheptane. The cycloalkylmay be unsubstituted, or substituted with one or more substituents.Typical, non-limiting examples of such substituents include C₁-C₆ alkyl,halogen, alkoxy, CN, COOH, CONH₂, OH, NH₂, NHCOCH₃, heterocyclyl,heteroaryl, aryl, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, -OSO ₂-aryl and thelike.

The term “heterocyclyl” as used herein refers to four to seven membercycloalkyl group containing one or more heteroatoms selected fromnitrogen, oxygen or sulfur. The heterocycloalkyl group optionallyincorporates one or more double or triple bonds, or a combination ofdouble bonds and triple bonds, but which is not aromatic. Typical,non-limiting examples of heterocycloalkyl groups include azetidine,pyrrolidine, 2-oxo-pyrrolidine, imidazolidin-2-one, piperidine, oxazine,thiazine, piperazine, piperazin-2,3-dione, morpholine, thiamorpholine,azapane, and the like. The heterocycloalkyl may be unsubstituted, orsubstituted with one or more substituents. Typical, non-limitingexamples of such substituents include C₁-C₆ alkyl, halogen, alkoxy, CN,COOH, CONH₂, OH, NH₂, NHCOCH₃, heterocyclyl, heteroaryl, aryl,SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl and the like.

The term “aryl” as used herein refers to a monocyclic or polycyclicaromatic hydrocarbon. Typical, non-limiting examples of aryl groupsinclude phenyl, naphthyl, anthracenyl, fluorenyl, phenanthrenyl, and thelike. The aryl group may be unsubstituted, or substituted with one ormore substituents. Typical, non-limiting examples of such substituentsinclude C₁-C₆ alkyl, halogen, alkoxy, CN, COOH, CONH₂, OH, NH₂, NHCOCH₃,heterocyclyl, heteroaryl, aryl, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,OSO₂-aryl and the like.

The term “heteroaryl” as used herein refers to a monocyclic orpolycyclic aromatic hydrocarbon group wherein one or more carbon atomshave been replaced with heteroatoms selected from nitrogen, oxygen, andsulfur. If the heteroaryl group contains more than one heteroatom, theheteroatoms may be the same or different. Typical, non-limiting exampleof heteroaryl groups include 1,2,4-oxadiazol, 1,3,4-oxadiazol,1,3,4-thiadiazol, 1,2,3,4-tetrazol, 1,3-oxazol, 1,3-thiazole, pyridine,pyrimidine, pyrazine, pyridazine, furan, pyrrol, thiophene, imidazole,pyrazole, benzofuran, benzothiophene, benzimidazole, benzoxazole,benzothiazole, thiazole, and the like. The heteroaryl group may beunsubstituted, or substituted with one or more substituents. Typical,non-limiting examples of such substituents include C₁-C₆ alkyl, halogen,alkoxy, CN, COOH, CONH₂, OH, NH₂, NHCOCH₃, heterocyclyl, heteroaryl,aryl, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl and the like.

The term “stereoisomers” as used herein refers to compounds that haveidentical chemical constitution, but differ with regard to thearrangement of their atoms or groups in space. The compounds of Formula(I) may contain asymmetric or chiral centers and, therefore, exist indifferent stereoisomeric forms. It is intended, unless specifiedotherwise, that all stereoisomeric forms of the compounds of Formula (I)as well as mixtures thereof, including racemic mixtures, form part ofthe present invention. In addition, the present invention embraces allgeometric and positional isomers (including cis and trans-forms), aswell as mixtures thereof, are embraced within the scope of theinvention. In general, a reference to a compound is intended to coverits stereoisomers and mixture of various stereoisomers.

The term “optionally substituted” as used herein means that substitutionis optional and therefore includes both unsubstituted and substitutedatoms and moieties. A “substituted” atom or moiety indicates that anyhydrogen on the designated atom or moiety can be replaced with aselection from the indicated substituent group, provided that the normalvalency of the designated atom or moiety is not exceeded, and that thesubstitution results in a stable compound.

The term “pharmaceutically acceptable salt” as used herein refers to oneor more salts of a given compound which possesses the desiredpharmacological activity of the free compound and which are neitherbiologically nor otherwise undesirable. In general, the“pharmaceutically acceptable salts” refer to salts that are suitable foruse in contact with the tissues of human and animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. (J. Pharmaceutical Sciences, 66: 1-19 (1977)), incorporated hereinby reference in its entirety, describes various pharmaceuticallyacceptable salts in details.

In general, the compounds according to the invention contain basic (e.g.nitrogen atoms) as well as acid moieties (e.g. compounds of Formula (I)wherein M is hydrogen). A person of skills in the art would appreciatethat such compounds, therefore, can form acidic salts (formed withinorganic and/or organic acids), as well as basic salts (formed withinorganic and/or organic bases). Such salts can be prepared usingprocedures described in the art. For example, the basic moiety can beconverted to its salt by treating a compound with a suitable amount ofacid. Typical, non-limiting examples of such suitable acids includehydrochloric acid, trifluoroacetic acid, methanesulphonic acid, or thelike. Alternatively, the acid moiety may be converted into its salt bytreating with a suitable base. Typical non-limiting examples of suchbases include sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate or the like. In case of compounds containing morethan one functional groups capable of being converted into salt, eachsuch functional group may be converted to salt independently. Forexample, in case of compounds containing two basic nitrogen atoms, onebasic nitrogen can form salt with one acid while the other basicnitrogen can form salt with another acid. Some compounds according tothe invention contain both, acidic as well as basic moieties, and thuscan form inner salts or corresponding zwitterions. In general, allpharmaceutically acceptable salt forms of compounds of Formula (I)according to invention including acid addition salts, base additionsalts, zwitterions or the like are contemplated to be within the scopeof the present invention and are generically referred to aspharmaceutically acceptable salts.

The term “halogen” or “halo” as used herein refers to chlorine, bromine,fluorine, or iodine.

The term “infection” or “bacterial infection” as used herein includespresence of bacteria, in or on a subject, which, if its growth wereinhibited, would result in a benefit to the subject. As such, the term“infection” in addition to referring to the presence of bacteria alsorefers to normal flora, which is not desirable. The term “infection”includes infection caused by bacteria.

The term “treat”, “treating” or “treatment” as used herein refers toadministering a medicament, including a pharmaceutical composition, orone or more pharmaceutically active ingredients, for prophylactic and/ortherapeutic purposes. The term “prophylactic treatment” refers totreating a subject who is not yet infected, but who is susceptible to,or otherwise at a risk of infection (preventing the bacterialinfection). The term “therapeutic treatment” refers to administeringtreatment to a subject already suffering from infection. The terms“treat”, “treating” or “treatment” as used herein also refer toadministering compositions or one or more of pharmaceutically activeingredients discussed herein, with or without additionalpharmaceutically active or inert ingredients, in order to: (i) reduce oreliminate either a bacterial infection or one or more symptoms of thebacterial infection, or (ii) retard the progression of a bacterialinfection or of one or more symptoms of the bacterial infection, or(iii) reduce the severity of a bacterial infection or of one or moresymptoms of the bacterial infection, or (iv) suppress the clinicalmanifestation of a bacterial infection, or (v) suppress themanifestation of adverse symptoms of the bacterial infection.

The term “pharmaceutically effective amount” or “therapeuticallyeffective amount” or “effective amount” as used herein refers to anamount, which has a therapeutic effect or is the amount required toproduce a therapeutic effect in a subject. For example, atherapeutically or pharmaceutically effective amount of an antibacterialagent or a pharmaceutical composition is the amount of the antibacterialagent or the pharmaceutical composition required to produce a desiredtherapeutic effect as may be judged by clinical trial results, modelanimal infection studies, and/or in vitro studies (e.g. in agar or brothmedia). The pharmaceutically effective amount depends on severalfactors, including but not limited to, the microorganism (e.g. bacteria)involved, characteristics of the subject (for example height, weight,sex, age and medical history), severity of infection and the particulartype of the antibacterial agent used. For prophylactic treatments, atherapeutically or prophylactically effective amount is that amountwhich would be effective in preventing a microbial (e.g. bacterial)infection.

The term “administration” or “administering” includes delivery of acomposition or one or more pharmaceutically active ingredients to asubject, including for example, by any appropriate methods, which servesto deliver the composition or its active ingredients or otherpharmaceutically active ingredients to the site of the infection. Themethod of administration may vary depending on various factors, such asfor example, the components of the pharmaceutical composition or thenature of the pharmaceutically active or inert ingredients, the site ofthe potential or actual infection, the microorganism involved, severityof the infection, age and physical condition of the subject and a like.Some non-limiting examples of ways to administer a composition or apharmaceutically active ingredient to a subject according to thisinvention includes oral, intravenous, topical, intrarespiratory,intraperitoneal, intramuscular, parenteral, sublingual, transdermal,intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal,gene gun, dermal patch, eye drop, ear drop or mouthwash. In case of apharmaceutical composition comprising more than one ingredient (activeor inert), one of way of administering such composition is by admixingthe ingredients (e.g. in the form of a suitable unit dosage form such astablet, capsule, solution, powder and a like) and then administering thedosage form. Alternatively, the ingredients may also be administeredseparately (simultaneously or one after the other) as long as theseingredients reach beneficial therapeutic levels such that thecomposition as a whole provides a synergistic and/or desired effect.

The term “growth” as used herein refers to a growth of one or moremicroorganisms and includes reproduction or population expansion of themicroorganism (e.g. bacteria). The term also includes maintenance ofon-going metabolic processes of a microorganism, including processesthat keep the microorganism alive.

The term, “effectiveness” as used herein refers to ability of atreatment or a composition or one or more pharmaceutically activeingredients to produce a desired biological effect in a subject. Forexample, the term “antibacterial effectiveness” of a composition or anantibacterial agent refers to the ability of the composition or theantibacterial agent to prevent or treat the microbial (e.g. bacterial)infection in a subject.

The term “synergistic” or “synergy” as used herein refers to theinteraction of two or more agents so that their combined effect isgreater than their individual effects.

The term “antibacterial agent” as used herein refers to any substance,compound or a combination of substances or a combination compoundscapable of: (i) inhibiting, reducing or preventing growth of bacteria;(ii) inhibiting or reducing ability of a bacteria to produce infectionin a subject; or (iii) inhibiting or reducing ability of bacteria tomultiply or remain infective in the environment. The term “antibacterialagent” also refers to compounds capable of decreasing infectivity orvirulence of bacteria.

The term “beta-lactam antibacterial agent” as used herein refers tocompounds with antibacterial properties and containing a beta-lactamnucleus in their molecular structure.

The term “beta-lactamase” as used herein refers to any enzyme or proteinor any other substance that breaks down a beta-lactam ring. The term“beta-lactamase” includes enzymes that are produced by bacteria and havethe ability to hydrolyze the beta-lactam ring in a beta-lactam compound,either partially or completely.

The term “beta-lactamase inhibitor” as used herein refers to a compoundcapable of inhibiting activity of one or more beta-lactamase enzymes,either partially or completely.

The term “pharmaceutically inert ingredient” or “carrier” or “excipient”refers to a compound or material used to facilitate administration of acompound, including for example, to increase the solubility of thecompound. Typical, non-limiting examples of solid carriers include,starch, lactose, dicalcium phosphate, sucrose, and kaolin and so on.Typical, non-limiting examples of liquid carriers include, sterilewater, saline, buffers, non-ionic surfactants, and edible oils such asoil, peanut and sesame oils and so on. In addition, various adjuvantscommonly used in the art may be included. These and other such compoundsare described in the literature, for example, in the Merck Index (Merck& Company, Rahway, N. J.). Considerations for inclusion of variouscomponents in pharmaceutical compositions are described, for example, inGilman et al. (Eds.) (1990); Goodman and Gilman's: The PharmacologicalBasis of Therapeutics, 8th Ed., Pergamon Press., which is incorporatedherein by reference in its entirety.

The term “subject” as used herein refers to vertebrate or invertebrate,including a mammal. The term “subject” includes human, animal, a bird, afish, or an amphibian. Typical, non-limiting examples of a “subject”includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs,rats, mice and guinea pigs.

The term “pharmaceutically acceptable derivative” as used herein refersto and includes any pharmaceutically acceptable salt, pro-drugs,metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes,enantiomers or adducts of a compound described herein which, uponadministration to a subject, is capable of providing (directly orindirectly) the parent compound. For example, the term “antibacterialagent or a pharmaceutically acceptable derivative thereof” includes allderivatives of the antibacterial agent (such as salt, pro-drugs,metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes,enantiomers or adducts) which, upon administration to a subject, iscapable of providing (directly or indirectly) the antibacterialcompound.

In general, the term “cation” includes Na, K, Mg, Ca, NH₄ ⁺, (CH₃CH₂)₃N⁺etc.

In one general aspect, there are provided compounds of Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof;

wherein:

R₁ is:

-   -   (a) SO₃M,    -   (b) SO₂NH₂,    -   (c) PO₃M,    -   (d) CH₂COOM,    -   (e) CF₂COOM,    -   (f) CHFCOOM, or    -   (g) CF₃;

M is hydrogen or a cation;

R₂ is:

-   -   (a) hydrogen,    -   (b) (CH₂)_(n)—R₃, or    -   (c) COOR₃,

n is 0, 1 or 2;

R₃ is:

-   -   (a) hydrogen,    -   (b) C₁-C₆ alkyl optionally substituted with one or more        substituents independently selected from halogen, OR₅, CN,        COOR₅, CONR₆R₇, NR₆R₇, NR₅COR₈, NR₅CONR₆R₇, heterocyclyl,        heteroaryl, cycloalkyl or aryl,    -   (c) CN,    -   (d) NR₆R₇,    -   (e) CONR₆R₇,    -   (f) NHCONR₆R₇,    -   (g) aryl optionally substituted with one or more substituents        independently selected from C₁-C₆ alkyl, OR₅, NR₆R₇, halogen,        CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or        NHCONR₆R₇,    -   (h) heterocyclyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇,    -   (i) heteroaryl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇,    -   (j) cycloalkyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇,    -   (k) cycloalkyl substituted with C₁-C₆ alkyl wherein C₁-C₆ alkyl        is further substituted with one or more substituents        independently selected from OR₅, NR₆R₇, halogen, CN, or CONR₆R₇,        or    -   (l) OR₈;

R₄ is:

-   -   (a) hydrogen,    -   (b) C₁-C₆ alkyl optionally substituted with one or more        substituents independently selected from halogen, OR₅, CN,        COOR₅, CONR₆R₇, NR₆R₇, NR₅COR₈, heterocyclyl, heteroaryl,        cycloalkyl or aryl,    -   (c) aryl optionally substituted with one or more substituents        independently selected from C₁-C₆ alkyl, OR₅, NR₆R₇, halogen,        CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or        NHCONR₆R₇,    -   (d) heterocyclyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇,    -   (e) heteroaryl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇, or    -   (f) cycloalkyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₆R₇;

R₅ and R₈ are each independently:

-   -   (a) hydrogen, or    -   (b) C₁-C₆ alkyl optionally substituted with one or more        substituents independently selected from halogen, CN, CONR₆R₇,        NR₆R₇, heterocyclyl, heteroaryl, cycloalkyl or aryl;

R₆ and R₇ are each independently:

-   -   (a) hydrogen,    -   (b) C₁-C₆ alkyl optionally substituted with one or more        substituents independently selected from halogen, OR₅, CN,        COOR₅, CONR₅R₈, NR₅R₈, NR₅COR₈, heterocyclyl, heteroaryl,        cycloalkyl or aryl,    -   (c) aryl optionally substituted with one or more substituents        independently selected from C₁-C₆ alkyl, OR₅, NR₅R₈, halogen,        CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or        NHCONR₅R₈,    -   (d) heterocyclyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₅R₈,    -   (e) heteroaryl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₅R₈,    -   (f) cycloalkyl optionally substituted with one or more        substituents independently selected from C₁-C₆ alkyl, OR₅,        NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl,        OSO₂-aryl, or NHCONR₅R₈, or    -   (g) R₆ and R₇ are joined together to form a four to seven member        ring.

Typical non-limiting examples of compounds according to the inventioninclude:

(2S,5R)-7-oxo-N-[(2S)-pyrrolidin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(2S,4R)-4-hydroxyl-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(2S,4R)-4-cyano-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(5R)-5-cyanopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(SR)-5-cyanopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(2S,4R)-4-trifluoroacetylamino-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(2S)-1-carbamimidoyl-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-{1-[(2S)-pyrrolidin-2-yl]ethyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-{[(2S)-5-oxopyrrolidin-2-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-[(2S)-azetidin-2-ylmethyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-[(2R)-azetidin-2-ylmethyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S ,5R)-7-oxo-N-(piperidin-4-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-((3R,S)-piperidin-3-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-((2R,S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-((2S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-((2S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-{1-[(2S)-piperidin-2-yl]ethyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S ,5R)-N-(azepan-2-ylmethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S)-N-(2,3-dihydro-1H-indol-2-ylmethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(2R,S)-1,2,3,4-tetrahydro-quinolin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(3S)-1,2,3,4-tetrahydro-isquinolin-3-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(4S)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl]methoxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(4S)-1H-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S)-N-1(4,5-dihydroxy-1,4-dihydropyridin-2-yl)methyloxyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-{[(4S)-2-(2-hydroxyphenyl)-4,5-dihydro-1,3-oxazol-4-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-{[(4S)-2-((2S)-pyrrolidin-2-yl)-4,5-dihydro-1,3-oxazol-4-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3R,S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(3R,5S)-5-cyanopyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(3S,5S)-5-cyanopyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-{[(3R,5S)-5-carbamoylpyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-(azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-methyloxy-7-oxo-N-(piperidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-methyloxy-7-oxo-N-(piperidin-3-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-methyloxy-7-oxo-N-(pyrrolidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-[(2S)-azetidin-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-hydroxy-7-oxo-N-[(2S)-pyrrolidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-hydroxy-7-oxo-N-[(2S)-piperidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-[(2S)-azepan-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-[(2R)-azetidin-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-hydroxy-7-oxo-N-[(2R)-pyrrolidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-hydroxy-7-oxo-N-[(2R)-piperidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-[(2R)-azepan-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

Typical, non-limiting examples of various salt forms of the compoundsaccording to the invention include:

Sodium salt of(2S,5R)-N-[(2S)-azetidin-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-hydroxy-7-oxo-N-[(2S)-pyrrolidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-hydroxy-7-oxo-N-[(2S)-piperidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-[(2S)-azepan-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-[(2R)-azetidin-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-hydroxy-7-oxo-N-[(2R)-pyrrolidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-hydroxy-7-oxo-N-[(2R)-piperidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-[(2R)-azepan-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-7-oxo-N-[(2S)-pyrrolidin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-{[(2S,4R)-4-hydroxyl-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-{[(2S,4R)-4-cyanol-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-{[(5R)-5-cyanopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S ,5R)-N-{[(SR)-5-cyanopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S ,5R)-N-{[(2S,5R)-4-trifluoroacetylamino-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-{[(2S)-1-carbamimidoyl-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-{[-1(2S)-pyrrolidin-2-yl]ethyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S ,5R)-7-oxo-N-{[(2S)-5-oxopyrrolidin-2-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-[(2S)-azetidin-2-ylmethyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-[(2R)-azetidin-2-ylmethyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-(piperidin-4-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-((3R,S)-piperidin-3-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-((2R,S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-((2S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-((2S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-{[-1(2S)-piperidin-2-yl]ethyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-(azepan-2-ylmethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S)-N-(2,3-dihydro-1H-indo1-2-ylmethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-{[(2R,S)-1,2,3,4-tetrahydro-quinolin-2-yl]methyloxy}7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-{[(3S)-1,2,3,4-tetrahydro-isquinolin-3-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-{[(4S)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl]methoxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-{[(4S)-1H-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S)-N-[(4,5-dihydroxy-1,4-dihydropyridin-2-yl)methyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S ,SR)-7-oxo-N-{[(4S)-2-(2-hydroxyphenyl)-4,5-dihydro-1,3-oxazol-4-yl]methyloxy}-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-{[(4S)-2-(2S)-pyrrolidin-2-yl)-4,5-dihydro-1,3-oxazol-4-yl]methyloxy} -6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-[(3R,S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,SR)-7-oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-{[(3R,5S)-5-cyanopyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S, 5R)-N-{[(3S,5S )-5-cyanopyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-{[(3R,5S)-5-carbamoylpyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-(azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-methyloxy-7-oxo-N-(piperidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-methyloxy-7-oxo-N-(piperidin-3-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-methyloxy-7-oxo-N-(pyrrolidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-(2-aminoethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidetrifluoroacetic acid salt;

(2S,5R)-N-(2-carbamimidamidoethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroacetic acid salt;

(2S,5R)-N-(3-aminopropyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidetrifluoroacetic acid salt;

(2S,5R)-N-{[(2S)-2,5-diaminopentyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroaceticacid salt;

(2S,5R)-N-{[(2S,4R)-4-aminopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroacetic acid salt;

(2S,5R)-7-oxo-N-[(2S)-piperazin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroaceticacid salt;

(2S,5R)-N-methyloxy-7-oxo-N-(piperazin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroaceticacid salt;

Sodium salt of(2S,5R)-N-methoxy-N-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium Salt of(2S,5R)-N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-[(1-methyl-1H-pyrazol-5-yl)methyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of(2S,5R)-N-hydroxy-N-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;or a stereoisomer thereof.

In general, the compounds of the invention can be prepared according tothe following procedures. A person of skills in the art would appreciatethat the described methods can be varied or optimized further to providethe desired and related compounds. In the following procedures, allvariables are as defined above.

As described in Scheme-1,trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid(1a), which is described PCT International Publication No. WO2009/091856, was reacted with corresponding substituted hydroxylaminesin presence of a suitable coupling agent such as EDC hydrochloride, ordicyclohexylcarbodiimide (DCC) in a suitable solvent such as N,Ndimethyl formamide; N,N dimethyl acetamide; 1,4 dioxane; chloroform;dichloromethane; or dichloroethane at a temperature ranging from −15° C.to 60° C. for about 1 to 24 hours to obtain intermediate compound (1b).

The intermediate compound (1b) was subjected for hydrogenolysis inpresence of a suitable catalyst (e.g. 5% or 10% palladium on carbon, or20% palladium hydroxide on carbon) in presence of hydrogen source (suchas hydrogen gas, ammonium formate, cyclohexene) in a suitable solvent(such as methanol, ethanol, methanol-dichloromethane mixture, or N,Ndimethyl formamide-dichloromethane mixture) at a temperature rangingfrom 25° C. to 60° C. for about 1 to 14 hours to obtain intermediatecompound (1c).

The intermediate compound (1c) was sulfonated by reacting it with asulfonating reagent (such as sulfur trioxide-pyridine complex, or sulfurtrioxide-N,N-dimethyl formamide complex) in a suitable solvent (such aspyridine, N,N-dimethyl formamide) at a temperature ranging from about25° C. to 90° C. for about 1 to 24 hours to obtain pyridine salt ofsulfonic acid which when treated with tetrabutyl ammonium sulfateprovided terabutylammonium salt of sulfonic acid as an intermediatecompound (1d).

Some compounds according to the invention were isolated as zwitterions,by treating intermediate compound (1d) with trifluoroacetic acid, in asuitable solvent (such as dichloromethane, chloroform, acetonitrile) ata temperature ranging from −10° C. to 40° C. for about 1 to 14 hours,especially when R in intermediate compound (1d) containedtert-butoxycarbonyl protected amine function.

Some other compounds according to the invention were isolated as asodium salt, by passing a solution of intermediate compound (1d) througha column of sodium form of Amberlite 200C resin in mixture oftetrahydrofuran-water followed by evaporation of the solvent undervacuum.

The required substituted hydroxyl amines were prepared as shown inScheme-2 as described in Synthesis 682-4(1976) and U.S. Pat. No.5,120,849 (1992)

In some embodiments, there are provided pharmaceutical compositionscomprising a compound of Formula (I), or a stereoisomer or apharmaceutically acceptable salt thereof.

In some other embodiments, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of acompound of Formula (I) or a stereoisomer or a pharmaceuticallyacceptable salt thereof.

In some embodiments, there is provided a method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of a compound of Formula (I) or a stereoisomer or apharmaceutically acceptable salt thereof.

In some other embodiments, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of apharmaceutical composition comprising a compound of Formula (I) or astereoisomer or a pharmaceutically acceptable salt thereof.

In some other embodiments, there is provided a method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of a pharmaceutical composition comprising a compoundof Formula (I) or a stereoisomer or a pharmaceutically acceptable saltthereof.

In some embodiments, there are provided pharmaceutical compositionscomprising: (a) a compound of Formula (I), or a stereoisomer or apharmaceutically acceptable salt thereof, and (b) at least onebeta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanicacid, or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided pharmaceuticalcompositions comprising: (a) a compound of Formula (I), or astereoisomer or a pharmaceutically acceptable salt thereof, and (b) atleast one antibacterial agent or a pharmaceutically acceptablederivative thereof.

In some other embodiments, there are provided pharmaceuticalcompositions comprising: (a) a compound of Formula (I), or astereoisomer or a pharmaceutically acceptable salt thereof, (b) at leastone beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof,and (c) at least one antibacterial agent or a pharmaceuticallyacceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of apharmaceutical composition comprising: (a) a compound of Formula (I), ora stereoisomer or a pharmaceutically acceptable salt thereof, and (b) atleast one beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of a pharmaceutical composition comprising: (a) acompound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, and (b) at least one beta-lactamase inhibitorselected from sulbactam, tazobactam, clavulanic acid, or apharmaceutically acceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of apharmaceutical composition comprising: (a) a compound of Formula (I), ora stereoisomer or a pharmaceutically acceptable salt thereof, and (b) atleast one antibacterial agent or a pharmaceutically acceptablederivative thereof.

In some other embodiments, there is provided a method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of a pharmaceutical composition comprising: (a) acompound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, and (b) at least one antibacterial agent or apharmaceutically acceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of apharmaceutical composition comprising: (a) a compound of Formula (I), ora stereoisomer or a pharmaceutically acceptable salt thereof, (b) atleast one beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof,and (c) at least one antibacterial agent or a pharmaceuticallyacceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of a pharmaceutical composition comprising: (a) acompound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, (b) at least one beta-lactamase inhibitorselected from sulbactam, tazobactam, clavulanic acid, or apharmaceutically acceptable derivative thereof, and (c) at least oneantibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of:(a) a compound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, and (b) at least one beta-lactamase inhibitorselected from sulbactam, tazobactam, clavulanic acid, or apharmaceutically acceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of: (a) a compound of Formula (I), or a stereoisomer ora pharmaceutically acceptable salt thereof, and (b) at least onebeta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanicacid, or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of:(a) a compound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, and (b) at least one antibacterial agent or apharmaceutically acceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of: (a) a compound of Formula (I), or a stereoisomer ora pharmaceutically acceptable salt thereof, and (b) at least oneantibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating bacterial infection in a subject, said method comprisingadministering to said subject a pharmaceutically effective amount of:(a) a compound of Formula (I), or a stereoisomer or a pharmaceuticallyacceptable salt thereof, (b) at least one beta-lactamase inhibitorselected from sulbactam, tazobactam, clavulanic acid, or apharmaceutically acceptable derivative thereof, and (c) at least oneantibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there is provided a method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of: (a) a compound of Formula (I), or a stereoisomer ora pharmaceutically acceptable salt thereof, (b) at least onebeta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanicacid, or a pharmaceutically acceptable derivative thereof, and (c) atleast one antibacterial agent or a pharmaceutically acceptablederivative thereof.

In some embodiments, there are provided methods for increasingantibacterial effectiveness of a antibacterial agent in a subject, saidmethod comprising co-administering said antibacterial agent or apharmaceutically acceptable derivative thereof with a pharmaceuticallyeffective amount of a compound of Formula (I) or a stereoisomer or apharmaceutically acceptable salt thereof.

In some embodiments, the compositions and methods according to theinvention use compounds of Formula (I) or a stereoisomer or apharmaceutically acceptable salt thereof in combination with at leastone antibacterial agent or a pharmaceutically acceptable derivativethereof. A wide variety of antibacterial agents can be used. Typical,non-limiting examples of antibacterial agents include one or more ofantibacterial compounds generally classified as aminoglycosides,Ansamycins, Carbacephems, Cephalosporins, Cephamycins, Lincosamides,Lipopeptides, Macrolides, Monobactams, Nitrofurans, Penicillins,Polypeptides, Quinolones, Sulfonamides, Tetracyclines, Oxazolidinone andthe like.

Typical, non-limiting examples of Aminoglycoside antibacterial agentsinclude Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin,Tobramycin, Paromomycin, Arbekacin, Streptomycin, Apramycin and thelike.

Typical, non-limiting examples of Ansamycin antibacterial agents includeGeldanamycin, Herbimycin and the like.

Typical, non-limiting examples of Carbacephem antibacterial agentsinclude Loracarbef and the like.

Typical, non-limiting examples of Carbapenem antibacterial agentsinclude Ertapenem, Doripenem, Imipenem, Meropenem and the like.

Typical, non-limiting examples of Cephalosporin and Cephamycinantibacterial agents include Cefazolin, Cefacetrile, Cefadroxil,Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin,Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole,Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam,Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cephamycin, Cefoxitin,Cefotetan, Cefmetazole, Carbacephem, Cefixime, Ceftazidime, Ceftriaxone,Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime,Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide,Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime,Oxacephem, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole,Ceftiofur, Cefquinome, Cefovecin, CXA-101, Ceftaroline, Ceftobiproleetc.

Typical, non-limiting examples of Lincosamide antibacterial agentsinclude Clindamycin, Lincomycin and the like.

Typical, non-limiting examples of Macrolide antibacterial agents includeAzithromycin, Clarithromycin, Dirithromycin, Erythromycin,Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin,Solithromycin and the like.

Typical, non-limiting examples of Monobactam antibacterial agentsinclude Aztreonam and the like.

Typical, non-limiting examples of Nitrofuran antibacterial agentsinclude Furazolidone, Nitrofurantoin and the like.

Typical, non-limiting examples of Penicillin antibacterial agentsinclude Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin,Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin,Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin,Ticarcillin and the like.

Typical, non-limiting examples of Polypeptide antibacterial agentsinclude Bacitracin, Colistin, Polymyxin B and the like.

Typical, non-limiting examples of Quinolone antibacterial agents includeCiprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomefloxacin,Moxifloxacin, Nalidixic acid, Levonadifloxacin, Norfloxacin, Ofloxacin,Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin and the like.

Typical, non-limiting examples of Sulfonamide antibacterial agentsinclude Mafenide, Sulfonamidochrysoidine, Sulfacetamide, Sulfadiazine,Sulfamethizole, Sulfamethoxazole, Sulfasalazine, Sulfisoxazole,Trimethoprim and the like.

Typical, non-limiting examples of Tetracycline antibacterial agentsinclude Demeclocycline, Doxycycline, Minocycline, Oxytetracycline,Tetracycline, Tigecycline and the like.

Typical, non-limiting examples of Oxazolidinone antibacterial agentsinclude Tedizolid, Linezolid, Ranbezolid, Torezolid, Radezolid etc.

The pharmaceutical compositions according to the invention may includeone or more pharmaceutically acceptable carriers or excipients or thelike, Typical, non-limiting examples of such carriers or excipientinclude mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin,sucrose, magnesium carbonate, wetting agents, emulsifying agents,solubilizing agents, pH buffering agents, lubricants, stabilizingagents, binding agents etc.

The pharmaceutical compositions according to this invention can exist invarious forms. In some embodiments, the pharmaceutical composition is inthe form of a powder or a solution. In some other embodiments, thepharmaceutical compositions according to the invention are in the formof a powder that can be reconstituted by addition of a compatiblereconstitution diluent prior to parenteral administration. Non-limitingexample of such a compatible reconstitution diluent includes water.

In some other embodiments, the pharmaceutical compositions according tothe invention are in the form of a frozen composition that can bediluted with a compatible diluent prior to parenteral administration.

In some other embodiments, the pharmaceutical compositions according tothe invention are in the form ready to use for parenteraladministration.

In the methods according to the invention, the pharmaceuticalcomposition and/or other pharmaceutically active ingredients disclosedherein may be administered by any appropriate method, which serves todeliver the composition or its constituents or the active ingredients tothe desired site. The method of administration can vary depending onvarious factors, such as for example, the components of thepharmaceutical composition and nature of the active ingredients, thesite of the potential or actual infection, the microorganism (e.g.bacteria) involved, severity of infection, age and physical condition ofthe subject. Some non-limiting examples of administering the compositionto a subject according to this invention include oral, intravenous,topical, intrarespiratory, intraperitoneal, intramuscular, parenteral,sublingual, transdermal, intranasal, aerosol, intraocular,intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop,ear drop or mouthwash.

The compositions according to the invention can be formulated intovarious dosage forms wherein the active ingredients and/or excipientsmay be present either together (e.g. as an admixture) or as separatecomponents. When the various ingredients in the composition areformulated as a mixture, such composition can be delivered byadministering such a mixture. The composition or dosage form wherein theingredients do not come as a mixture, but come as separate components,such composition/dosage form may be administered in several ways. In onepossible way, the ingredients may be mixed in the desired proportionsand the mixture is then administered as required. Alternatively, thecomponents or the ingredients (active or inert) may be separatelyadministered (simultaneously or one after the other) in appropriateproportion so as to achieve the same or equivalent therapeutic level oreffect as would have been achieved by administration of the equivalentmixture.

Similarly, in the methods according to the invention, the activeingredients disclosed herein may be administered to a subject in severalways depending on the requirements. In some embodiments, the activeingredients are admixed in appropriate amounts and then the admixture isadministered to a subject. In some other embodiments, the activeingredients are administered separately. Since the inventioncontemplates that the active ingredients agents may be administeredseparately, the invention further provides for combining separatepharmaceutical compositions in kit form. The kit may comprise one ormore separate pharmaceutical compositions, each comprising one or moreactive ingredients. Each of such separate compositions may be present ina separate container such as a bottle, vial, syringes, boxes, bags, andthe like. Typically, the kit comprises directions for the administrationof the separate components. The kit form is particularly advantageouswhen the separate components are preferably administered in differentdosage forms (e.g., oral and parenteral) or are administered atdifferent dosage intervals. When the active ingredients are administeredseparately, they may be administered simultaneously or sequentially.

The pharmaceutical composition or the active ingredients according tothe present invention may be formulated into a variety of dosage forms.Typical, non-limiting examples of dosage forms include solid,semi-solid, liquid and aerosol dosage forms; such as tablets, capsules,powders, solutions, suspensions, suppositories, aerosols, granules,emulsions, syrups, elixirs and a like.

In general, the pharmaceutical compositions and method disclosed hereinare useful in preventing or treating bacterial infections.Advantageously, the compositions and methods disclosed herein are alsoeffective in preventing or treating infections caused by bacteria thatare considered to be less or not susceptible to one or more of knownantibacterial agents or their known compositions. Some non-limitingexamples of such bacteria known to have developed resistance to variousantibacterial agents include Acinetobacter, E. coli, Pseudomonasaeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacterand a like. Other non-limiting examples of infections that may beprevented or treated using the compositions and/or methods of theinvention include: skin and soft tissue infections, febrile neutropenia,urinary tract infection, intraabdominal infections, respiratory tractinfections, pneumonia (nosocomial), bacteremia meningitis, surgical,infections etc.

Surprisingly, the compounds, compositions and methods according to theinvention are also effective in preventing or treating bacterialinfections that are caused by bacteria producing one or morebeta-lactamase enzymes. The ability of compositions and methodsaccording to the present invention to treat such resistant bacteria withtypical beta-lactam antibiotics represents a significant improvement inthe art.

In general, the compounds of Formula (I) or a stereoisomer orpharmaceutically acceptable salt thereof according to invention are alsouseful in increasing antibacterial effectiveness of a antibacterialagent in a subject. The antibacterial effectiveness of one or moreantibacterial agents may increased, for example, by co-administeringsaid antibacterial agent or a pharmaceutically acceptable salt thereofwith a pharmaceutically effective amount of a compound of Formula (I) ora stereoisomer or a pharmaceutically acceptable salt thereof accordingto the invention.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention. Forexample, those skilled in the art will recognize that the invention maybe practiced using a variety of different compounds within the describedgeneric descriptions.

EXAMPLES

The following examples illustrate the embodiments of the invention thatare presently best known. However, it is to be understood that thefollowing are only exemplary or illustrative of the application of theprinciples of the present invention. Numerous modifications andalternative compositions, methods, and systems may be devised by thoseskilled in the art without departing from the spirit and scope of thepresent invention. The appended claims are intended to cover suchmodifications and arrangements. Thus, while the present invention hasbeen described above with particularity, the following examples providefurther detail in connection with what are presently deemed to be themost practical and preferred embodiments of the invention.

Example-1(2S,5R)-7-oxo-N-[(2S)-pyrrolidin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Preparation of side chain: tert-butyl(2S)-2-[(aminooxy)methyl]pyrrolidine-1 carboxylate:

Step-1

A solution of DEAD (17.14 ml, 1.092 mol) in THF (366 ml) was cooled to−10° C. and to this was added slowly a solution of TPP (22.49 gm, 1.092mmol) in THF (36 ml). After stirring for 45 minutes below −10° C., asolution of tert-butyl (2S)-2-(hydroxymethyl) pyrrolidine-l-carboxylate(12.2 gm, 0.606 mol) in THF (36 ml) was added and after stirring for 5minutes a solution of N-Hydroxy phthalimide (9.88 gm, 0.606 mol) in THF(122 ml) was added. The resulting mixture was allowed to warm to RT andstirring continued further. After 16 hours, the solvent was evaporatedunder reduced pressure and the residue diluted with ethyl acetate (250ml) and the ethyl acetate layer washed with sat. aqueous sodiumbicarbonate solution (1×122 ml), water (1×122 ml) and Brine (1×61 ml).The solvent was evaporated under reduced pressure and the residue waspurified by column chromatography, over silica gel. Elution with 12%Acetone in hexane and the concentration of the combined fractions gavethe product as pale yellow oil, 20.6 gm, in 98% yield.

Analysis:

Mass: 347.3 (M+H) for MW-346.39 and M.-C₁₈H₂₂N₂O₅

Step-II:

To a solution of the Phthalimide (4 gm, 0.115 mol) in ethanol (60 ml )and was added hydrazine hydrate (0.84 ml, 0.173 mol) at RT. Afterstirring for 1 hour the insolubles were separated by filtration. Thefiltrate was concentrated under reduced pressure and the residue wasdiluted with DCM (40 ml). The DCM layer was washed with water (2×40 ml)and brine (1×40 ml). The solvent was evaporated under reduced pressureto obtain 2.4 gm residue. This was used as such for the next couplingreaction.

Coupling Reaction

Step-1: Preparation of(2S,5R)-2-[(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-methyloxycarbamoyl]-(2S)-pyrrolidine-1-carboxylicacid tert-butyl ester:

To a clear solution of(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (3.06 gm, 0.111 mol) in N,N-dimethyl formamide (24 ml), was addedHOBt (1.49 gm, 0.111 mol) followed by EDC hydrochloride (3.18 gm, 0.166mol) and NMM(3.39, 0.333 mol) at about 25° C. to 35° C. under stirring.The reaction mixture was stirred for 15 minutes and a solution of2-Aminooxymethyl-(S)-pyrrolidine-1-carboxylic acid t-butyl ester (2.4gm, 0.100 mol) dissolved in N,N-dimethyl formamide (15 ml). The reactionmixture was stirred at a temperature between 25° C. to 35° C. for 16hours and the resulting mixture was poured into water (120 ml) andmixture extracted with Ethyl acetate (3×25 ml). The ethyl acetate layerwas washed with water (1×100 ml) and brine (13×50 ml). The solvent wasevaporated under reduced pressure and the residue was purified by columnchromatography over silica gel. Elution with 10% acetone in hexane andconcentration of the combined fractions gave the product as a whitesolid, 2.1 gm, 64% yield.

Analysis:

Mass: 475.4 (M+H) for MW-474.56 and M.F-C₂₄H₃₄N₄O₆

¹H NMR: Solvent(CDCl₃): 10.16 (s, 1H), 7.43-7.35 (m, 5H), 5.06-4.88 (dd,2H), 4.12 (s, 1H), 3.94-0.393 (d, 2H), 3.83 (unresolved s, 1H),3.75-3.73 (m, 1H), 3.37-3.28 (dt, 2H), 3.02-2.86 (dd, 2H), 2.29-2.25 (m,1H), 1.99-1.82 (m, 5H), 1.75-1.61 (m, 2H), 1.45 (s, 9H).

Step-2: Preparation of tetrabutylammonium salt of(2S,5R)-2-[(6-sulfooxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-methyloxycarbamoyl]-(2S)-pyrrolidine-1-carboxylicacid tert-butyl ester:

A solution of the Benzyl compound (2.1 g, mmol) in 1:1 mixture of DMF:DCM (5 ml), was hydrogenated over 10% Pd/C (125 mg) over 1 atmosphere ofHydrogen balloon. After stirring for 4 hours the reaction mixture wasfiltered over celite. The filtrate was concentrated under reducedpressure and the residue obtained was dissolved in fresh DMF (2.5 ml)and cooled to 10° C.SO₃.DMF complex (193 mg, 12.6 mmol) was added andthe reaction mixture was allowed to warm to RT. After stirring RM at RTfor 1.5 hours, TBAA (379 mg, 12.6 mmol) in water (1.25 ml) was added tothe reaction mixture and stirring continued further for 2hours. Thevolatiles were removed by high vacuum distillation and the residueco-evaporated with xylene (2×25 ml) to remove traces of DMF. The residueobtained was diluted with water (20ml) and extracted with DCM (3×20 ml).The combined DCM layer was washed with water (2×20 ml). The DCM layerwas dried and the solvent evaporated under reduced pressure. The cruderesidue was triturated with Diethyl ether (3×25 ml) to obtain theproduct as a white solid, 610 mg, 82% yield.

Analysis:

Mass: 463.4 (M-H) for MW-705.96 and M.F,-C₃₃H₆₃N₅O₉S.

¹H NMR: Solvent(CDCl₃): 10.2 (s, 1H), 4.35 (s, 1H), 4.14 (s, 1H),3.91-3.92 (d, 2H), 3.74 (m, 1H), 3.36-3.27 (m, 10H), 2.96-2.88 (dd, 2H),2.31-2.26 (m, 2H), 2.19-1.98 (m, 2H), 1.95-1.70 (m, 4H), 1.68-1.62 (p,8H), 1.49-1.40 (m, 17H), 1.02-0.98 (t, 12H).

Step-3: Preparation of(2S,5R)-7-oxo-N-1(2S)-pyrrolidin-2-ylmethyloxyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide:

To a cooled (−10° C.) solution of TBA compound (300 mg, 42 mmol) in DCM(2.5 ml) was added TFA (2.5 ml). After stirring for 30 min. at −10° C.the solvent was evaporated under reduced pressure. The residue obtainedwas triturated with diethyl ether to obtain white solid. The solid waswashed with diethyl ether (3×25 ml), Acetonitrile (2×25 ml) and DCM(2×25 ml). And the residual solid dried under reduced pressure (4 mmHg),to obtain the product as a white solid 140 mg, 91% yield.

Analysis:

Mass: 363.2 (M-H) for MW-364.37 and M.F-C₁₂H₂₀N₄O₇S.

¹H NMR: Solvent(DMSO-D6):11.73 (s, 1H), 8.62-8.83 (d, 2H), 3.88-4.00 (m,3H), 3.74-3.81 (m, 2H), 3.19 (t, 2H), 2.94-3.04 (dd, 2H), 1.96-2.03 (m,2H), 1.80-1.92 (m, 3H), 1.54-1.73 (m, 3H).

Examples 2 to 39 (Table 1) were prepared using the procedure describedas in Example-1 and using corresponding R₁CH₂ONH₂, in place of2-Aminooxymethyl-(S)-pyrrolidine-1-carboxylic acid t-butyl ester. Thesecompounds were isolated as zwitterions.

Examples 40 to 45 (Table 2) were prepared using the procedure describedas in Example-1 and using corresponding R₁CH₂ONH₂, in place of2-Aminooxymethyl-(S)-pyrrolidine-1-carboxylic acid t-butyl ester. Thesecompounds were isolated as Trifluoroacetic acid salts

Examples 46 to 50 (Table 3) were prepared using the procedure describedas in Example-1 and using corresponding R₁CH₂ONH₂, in place of2-Aminooxymethyl-(S)-pyrrolidine-1-carboxylic acid t-butyl ester. Thesecompounds were isolated as sodium salts.

Procedure: A solution of intermediate sulphate compound (1d) was passedthrough a column of sodium form of Amberlite 200C resin in mixture oftetrahydrofuran-water followed by evaporation of the solvent from thecombined fractions under reduced pressure (4 mmHg).

TABLE 1 Ex- am- Mass (ES-1) ple as free acid No. R1 R2 R3 ¹H-NMR(DMSO-d₆)/D₂O, δ values (MF) 1. SO₂OH H

(DMSO-d₆): δ 11.73 (s, 1H), 8.62-8.83 (d, 2H), 3.88- 4.00 (m, 3H),3.74-3.81 (m, 2H), 3.19 (t, 2H), 2.94- 3.04 (dd, 2H), 1.96-2.03 (m, 2H),1.80-1.92 (m, 3H), 1.54-1.73 (m, 3H). 363.1 (C₁₂H₂₀N₄O₇S) 2. SO₂OH H

(DMSO-d₆): δ 11.72 (br s, 1H), 8.88 (br s, 1H), 8.60 (br s, 1H),3.88-4.04 (m, 3H), 3.72-3.84 (m, 2H), 2.96-3.28 (m, 4H), 1.52-2.10 (s,8H). 363.1 (M − 1) C₁₂H₂₀N₄O₇S 3. SO₂OH H

(DMSO-d₆): δ 11.50 (br s, 1H), 8.60 (br s, 2H), 3.98-4.02 (m, 1H),3.68-3.82 (m, 3H), 3.30-3.40 (m, 1H), 2.96-3.26 (m, 5H), 2.54-2.60 (m,1H), 1.94-2.08 (m, 2H), 1.84-1.88 (m, 1H), 1.64- 1.78 (s, 3H). 363.1 (M− 1) C₁₂H₂₀N₄O₇S 4. SO₂OH H

(DMSO-d₆): δ 11.50 (br s, 1H), 8.60 (br s, 2H), 3.98-4.02 (m, 1H),3.69-3.84 (m, 3H), 2.96-3.36 (m, 6H), 2.54-2.60 (m, 1H), 1.94-2.08 (m,2H), 1.82-1.90 (m, 1H), 1.60-1.72 (s, 3H). 363.1 (M − 1) C₁₂H₂₀N₄O₇S 5.SO₂OH H

— 379.1 (C₁₂H₂₀N₄O₈S) 6. SO₂OH H

— 388.1 (C₁₃H₁₉N₅O₇S) 7. SO₂OH H

— 388.1 (C₁₃H₁₉N₅O₇S) 8. SO₂OH H

— 388.1 (C₁₃H₁₉N₅O₇S) 9. SO₂OH H

(DMSO-d₆): δ 11.6 (s, 1H), 9.75 (d, 1H), 8.91- 9.21 (bs, 2H), 4.40-4.46(q, 1H), 4.02 (s, 2H), 3.86 (bs, 1H), 3.52-3.79 (d, 1H), 3.47-3.49 (t,1H), 3.12-3.19 (m, 2H), 3.02-3.052 (d, 1H), 2.94-2.96 (d, 1H), 2.38-2.45(m, 1H) 2.003- 2.054 (m, 1H), 1.87-1.89 (m, 1H), 1.58-1.74 (m, 2H),1.54-1.58 (m, 2H). [ES−] 473.9 [ES+] 476.0 (C₁₄H₂₀N₅O₈SF₃) 10. SO₂OH H

(DMSO-d₆) δ: 10.9 (s, 1H), 7.65 (d, 3H), 4.23 (s, 1H), 4.403 (m, 2H),3.87-3.92 (m, 2H), 3.70-3.74 (dd, 1H), 3.47-3.50 (m, 1H), 2.91- 3.02(dd, 2H), 1.83-1.89 (m, 6H), 1.65-1.67 (m, 2H). 405.15 (C₁₃H₂₂N₆O₇S) 11.SO₂OH H

(DMSO-d₆): 12.04 (bs, 1H), 8.42-9.20 (bs, 2H), 4.09 (bs, 1H), 4.01 (s,1H), 3.83 (m, 1H), 3.67 (m, 1H), 3.21 (m, 2H), 2.92-3.03 (m, 2H),1.69-2.05δ (m, 8H), 1.23-1.24 (d, 3H), [ES⁻] 377.0, [ES⁺] 379.0(C₁₃H₂₂N₄O₇S) 12. SO₂OH H

— 377.1 (C₁₂H₁₈N₄O₈S) 13. SO₂OH H

— 350.1 (M + 1) (C₁₁H₁₈N₄O₇S) 14. SO₂OH H

— 350.1 (M + 1) (C₁₁H₁₈N₄O₇S) 15. SO₂OH H

(DMSO-d₆) δ 11.37 (s, 1H), 8.39 (bs, 1H), 8.1 (bs, 1H), 3.98 (s, 1H),3.67-3.68 (d, 2H), 3.64- 3.69 (d, 2H), 3.24-3.27 (d, 1H), 3.07-3.12 (m,1H), 2.99 (s, 2H), 2.8-2.89 (m, 2H), 1.85-1.96 (m, 4H), 1.65-1.67 (m,2H), 1.55 (m, 1H), [ES⁻] 377.2 [ES⁺] 379.0 (C₁₃H₂₃N₄O₇S) 1.28-1.36 (m,2H). 16. SO₂OH H

(DMSO-d₆): δ 11.43 (s, 1H), 8.48-8.50 (d, 1H), 8.24-8.27 (d, 1H), 3.99(s, 1H), 3.61-3.73 (m, 3H), 3.34-3.37 (m, 2H), 3.16-3.21 (m, 2H), 2.99(s, 2H), 2.68-2.77 (m, 3H), 1.85-2.00 (m, 4H), 1.65-1.79 (m, 4H),1.53-1.58 (m, 2H), 1.20-1.30 (m, 2H). 378.40 (C₁₃H₂₂N₄O₇S) 17. SO₂OH H

(DMSO-d₆): δ 11.85 (br s, 1H), 11.77 (br s, 1H), 8.47 (br s, 1H),4.00-4.04 (m, 1H), 3.80- 3.95 (m, 3H), 2.76-3.18 (m, 4H), 1.98-2.06 (m,1H), 1.84-1.94 (m, 1H), 1.62-1.80 (m, 5H), 1.28- 1.60 (m, 4H). 377.2 (M− 1) (C₁₃H₂₂N₄O₇S) 18. SO₂OH H

(DMSO-d₆): δ 11.78 (s, 1H), 8.36-8.60 (m, 2H), 3.76-4.06 (m, 4H),2.70-3.06 (m, 4H), 1.98-2.04 (m, 1H), 1.84-1.92 (m, 1H), 1.62-1.80 (m,5H), 1.28-1.60 (m, 4H). 377.0 (M − 1) (C₁₃H₂₂N₄O₇S) 19. SO₂OH H

(DMSO-d₆): δ 11.90 (s, 1H), 8.40-8.60 (m, 2H), 3.76-4.06 (m, 4H),2.70-3.06 (m, 4H), 1.98-2.04 (m, 2H), 1.84-1.92 (m, 1H), 1.62-1.80 (m,5H), 1.28-1.60 (m, 4H). 379.0 (M + 1) (C₁₃H₂₂N₄O₇S) 20. SO₂OH H

(DMSO-d₆): δ 11.78 (s, 1H), 8.16-8.60 (m, 2H), 3.98-4.03 (m, 3H),3.78-3.80 (d, 1H), 3.23-3.28 (m, 4H), 2.85-3.06 (m, 4H), 1.94-2.05 (m,2H), 1.57-1.87 (m, 8H), 1.30-1.49 (m, 3H), 1.15- 1.24 (m, 4H). 391.0 (M− 1) (C₁₄H₂₄N₄O₇S) 21. SO₂OH H

— 391.2 (M − 1) (C₁₄H₂₄N₄O₇S) 22. SO₂OH H

(DMSO-d₆ D₂O exchange): δ 11.5 (M, 1H), 7.128-7.012 (m, 2H), 6.76 (m,2H), 4.12 (m, 1H) 3.98 (s, 1H), 3.90-3.73 (m, 3H), 3.14- 3.08 (dd, 2H),2.99 (d, 2H), 2.78-2.72 (m, 1H) 2.00- 411.3 (M − 1) 413.3 (M + 1)(C₁₆H₂₀N₄O₇S) 1.98 (m, 1H), 1.85 (m, 1H), 1.71-1.66 (m, 2H). 23. SO₂OH H

(DMSO-d₆, D₂O exchange): δ 6.96-6.99 (m, 2H), 6.68-6.73 (m, 2H), 3.98(d, 1H), 3.90 (dd, 1H) 3.72-3.77 (m, 2H), 3.45-3.55 (m, 1H), 3.05 (d,1H), 2.91 (dd, 1H), 2.66-2.71 (m, 2H), 425.2 (M − 1) 427.2 (M + 1)(C₁₇H₂₂N₄O₇S) 1.97-2.04 (m, 1H), 1.85-1.88 (m, 2H), 1.65- 1.71 (m, 2H),1.53-1.58 (m, 1H). 24. SO₂OH H

(DMSO-d₆): δ 11.91 (s, 1H), 9.18 (br s, 1H), 7.19-7.27 (m, 4H), 4.33(dd, 2H), 3.83-4.11 (m, 4H), 2.99-3.08 (m, 2H), 2.94 (d, 1H), 2.83 (dd,1H), 2.02-2.05 (m, 1H), 1.86-1.90 (m, 1H), 425.0 (M − 1) (C₁₇H₂₂N₄O₇S)1.65-1.76 (m, 2H). 25. SO₂OH H

(DMSO-d₆): δ 11.86 (br s, 1H), 9.90 (br s, 1H), 7.29 (s, 1H), 4.89 (dd,1H), 4.46 (dd, 2H), 4.12 (dd, 1H), 4.01-4.05 (m, 2H), 3.83 (d, 1H), 3.75(s, 3H), 2.98 (dd, 2H), 1.96-2.06 (m, 1H), 1.86-1.99 (m, 1H) 1.63-1.77(m, 2H). 45.1 (M − 1) 417.1 (M + 1) (C₁₄H₂₀N₆O₇S) 26. SO₂OH H

— 401.1 (M − 1) 403.1 (M + 1) (C₁₃H₁₈N₆O₇S) 27. SO₂OH H

— 404.2 (M − 1) (C₁₃H₁₇N₄O₉S) 28. SO₂OH H

(DMSO-d₆ D₂O exchange) δ 7.50-7.52 (m, 1H), 7.33-7.37 (m, 1H), 6.91-6.94(m, 2H), 4.25-4.31 (m, 3H), 4.15-4.17 (m, 1H) 3.97-4.05 (m, 2H),3.05-2.95 (dd, 3H), 2.05-.97 (m, 2H), 1.82-1.85 (m, 3H), 1.66-1.62 (m,2H). 457.2 (M + 1) (C₁₇H₂₀N₄O₉S) 29. SO₂OH H

(DMSO-d₆ D₂O exchange) δ 7.41 (d, 1H), 4.20- 4.14 (m, 3H), 4.02-3.99 (m,2H), 3.86-3.82 (dd, 1H) 3.75-3.74 (m, 1H), 3.68-3.64 (dd, 1H), 3.21-3.02 (m, 4H) 2.93-2.90 (d, 1H) 2.24- 2.19 (m, 2H), 2.00-1.68 (m, 7H)432.1 (M − 1) 434.2 (M + 1) (C₁₅H₂₃N₅O₈S) 30. SO₂OH H

(D₂O): δ 4.733 (m, 1H), 4.107 (d, 1H), 4.001 (d, 1H), 3.516-3.481 (d,1H), 3.371 (4H, m), 3.240-3.210 (d, 1H), 2.258-2.220 (1H, m),2.130-1.936 (3H, m), 1.897-1.712 (2H, m). 350.9 (M + 1) (C₁₁H₁₈N₄O₇S)31. SO₂OH H

— 350.9 (M + 1) (C₁₁H₁₈N₄O₇S) 32. SO₂OH H

— 350.9 (M + 1) (C₁₁H₁₈N₄O₇S) 33. SO₂OH H

(DMSO-d₆): δ 11.62 (s, 1H), 9.77 (bs, 1H), 4.802-4.83 (q, 1H), 4.68 (s,1H), 4.001 (s, 1H), 3.78-3.79 (d, 1H), 3.56-3.59 (d, 1H), 3.12-3.16 (m,1H), 3.07 (s, 2H), 2.55-2.61 (m, 1H), 2.43- 2.44 (d, 1H), 2.40-2.41 (d,1H), 1.97-1.99 (m, 1H), 1.86-1.975 (m, 1H), 1.66-1.71 (m, 2H). [ES−]373.9, [ES+] 376.0 (C₁₂H₁₇N₅O₇S) 34. SO₂OH H

— [ES−] 373.9, [ES+] 376.0 (C₁₂H₁₇N₅O₇S) 35. SO₂OH H

(DMSO-d₆): δ 11.38 (s, 1H), 9.44 (bs, 1H), 8.49 (bs, 1H), 7.90 (s, 1H),7.70 (s, 1H), 4.63 (s, 1H), 4.20 (s, 1H), 3.99 (s, 1H), 3.77-3.78 (d,1H), 3.54-3.57 (d, 1H), 3.02-3.14 (m, 1H), 2.99-3.02 (d, 1H), 2.92-2.95(d, 1H), 2.55-2.60 [ES−] 391.8, [ES+] 394.1 (C₁₂H₁₉N₅O₈S) (m, 1H),2.10-2.11 (d, 1H), 2.05-2.067 (m, 1H), 1.85 (m, 1H), 1.61-1.72 (m, 1H),1.55-1.61 (m, 1H). 36 SO₂OH H

(DMSO-d₆): δ 11.8 (bs, 1H), 8.85 (bs, 1H), 8.52 (bs, 1H), 4.73 (m, 1H),4.17 (m, 2H), 4.00 (m, 3H), 3.79 (d, 1H), 2.91-3.02 (m, 2H), 2.00 (m,1H), 1.86 (m, 1H), 1.64-1.71 (m, 2H). [ES⁺] 336.9 (C₁₀H₁₆N₄O₇S) 37.SO₂OH

CH₃ (DMSO-d₆): δ 8.2-8.24 (d, 2H), 4.02 (s, 1H), 3.730 (m, 1H), 3.561(s, 3H), 3.18-3.37 (m, 3H), 2.72-2.78 (m, 3H), 2.48-2.56 (m, 2H),1.95-1.96 (m, 2H), 1.726-1.787 (m, 3H), 1.55- 1.59 (m, 2H), 1.07-1.17(m, 2H). 392.42 (C₁₄H₂₄N₄O₇S) 38. SO₂OH

CH₃ (DMSO-d₆): δ 8.4 (bs, 1H), 8.08 (bs, 1H), 4.31 (bs, 1H), 4.01 (s,1H), 3.6.2-3.72 (m, 4H), 3.44- 3.48 (m, 1H), 3.23 (bs, 3H), 2.97 (d,1H), 2.84 (bs, 2H), 1.76-1.89 (m, 6H), 1.22-1.33 (m, 2H). [ES−] 391.3,[ES+] 393.3 (C₁₄H₂₄N₄O₇S) 39. SO₂OH

CH₃ (DMSO-d₆): δ 8.95 (bs, 1H), 8.38 (bs, 1H), 4.33 (m, 1H), 4.03 (m,2H), 3.65-3.90 (m, 5H), 3.00- 3.24 (m, 4H), 2.03-2.09 (m, 1H), 1.73-1.91(m, 5H), 1.26-1.31 (m, 2H), [ES⁻] 377.3, [ES⁺] 379.2 (C₁₃H₂₂N₄O₇S)

TABLE 2 40. SO₂OH H

(DMSO-d₆): δ 11.64 (s, 1H), 7.78 (bs, 3H), 4.01 (s, 1H), 3.95 (t, 2H),3.82 (d, 1H), 2.95-3.02 (m, 3H), 2.92 (d, 1H), 1.89-2.04 (m, 1H),1.85-1.88 (m, 1H), 1.61-1.75 (m, 2H). 323.1 (C₉H₁₆N₄O₇S) 41. SO₂OH H

(DMSO-d₆): δ 8.18 (t, 1H), 7.59 (bs, 5H), 3.98 (s, 1H), 3.81 (t, 2H),3.74 (d, 1H), 3.38 (t, 2H), 2.99-3.02 (d, 1H), 2.82-2.85 (d, 1H),2.05-2.08 (dd, 1H), 1.84-1.86 (m, 1H), 1.56-1.69 (m, 2H). 365.1(C₁₀H₁₈N6O₇S) 42. SO₂OH H

(DMSO-d₆): δ 11.63 (s, 1H), 7.72 (bs, 3H), 4.00 (s, 1H), 3.88 (t, 2H),3.75 (d, 1H), 2.95-3.00 (m, 4H), 1.99 (d, 1H), 1.78-1.92 (m, 3H),1.62-1.73 (m, 2H). 337 (C₁₀H₁₈N₄O₇S) 43. SO₂OH H

(DMSO-d₆): δ 11.79 (br, 1H), 7.94-7.663 (br, 5H), 4.02 (s, 1H), 3.94 (m,1H), 3.81 (m, 1H), 3.05-2.95 (dd, 2H), 2.75 (m, 2H), 2.06-1.88 (m, 2H),1.68 (m, 2H), 1.50 (m, 4H), 1.35 (m, 2H). (M − H, 394 (−SO₃H)(C₁₃H₂₆N₅O₇S•C₂O₂F₃) 44. SO₂OH H

(DMSO-d₆): δ 9.00 (bs, 2H), 8.05 (bs, 3H), 3.98-4.07 (m, 3H), 3.80-3.84(t, 2H), 3.45-3.50 (dd, 1H), 3.15- 3.20 (m, 1H), 3.03-3.06 (d, 1H),2.93-2.96 (d, 1H), 2.41-2.47 (m, 1H), 2.01-2.05 (m, 1H), 1.88-1.90 (m,1H), 1.52-1.75 (m, 6H). 378.2 (C₁₂H₂₁N₅O₇S) 45. SO₂OH H

(DMSO-d₆): δ 11.9 (s, 1H), 9.00 (bs, 2H), 3.94-4.02 (s, 1H), 3.79-3.80(m, 1H), 3.44-3.59 (m, 4H), 3.03- 3.16 (m, 4H), 2.99 (s, 2H), 1.99-2.03(m, 1H), 1.88- 1.91 (m, 1H), 1.65-1.75 (m, 2H), 1.53-1.55 (m, 1H),1.26-1.32 (m, 1H). [ES⁻] 378.2, [ES⁺] 380.1 for free amineC₁₂H₂₁N₅O₇S•C₂HO₂F₃ 46. SO₂OH

CH₃ (DMSO-d₆): δ 8.2-9.6 (bs, 3H), 4.38 (m, 1H), 4.01 (m, 2H), 3.69 (m,4H), 3.33-3.58 (m, 4H), 2.92-3.31 (m, 5H), 2.70- 2.91 (m, 1H), 1.50-1.95(m, 4H). C₁₃H₂₄N₅O₇S•C₂O₂F₃ [ES⁻] 392.2, [ES⁺] 394.3

TABLE 3 47. SO₂ONa CH₃ CH₃ (DMSO-d₆): δ 4.38 (m, 1H), 4.15-4.20 (m, 2H),3.58-3.78 (m, [ES⁻] 308.1, [ES⁺] 4H), 3.15-3.42 (m, 4H), 1.83-2.04δ (m,4H) 310.1 for free acid (C₉H₁₄N₃O₇S•Na) 48. SO₂ONa H CH₃ (DMSO-d₆): δ11.39 (s, 1H), 3.97 (s, 1H), 3.66 (d, 1H), 3.57 294 for free acid (s,3H), 2.99 (dd, 2H), 1.95-1.97 (m, 1H), 1.79-1.88 (m, 1H), C₈H₁₂N₃O₇S•Na1.62-1.72 (m, 2H). 49. SO₂ONa H H (D₂O): δ 4.10-4.22 (m, 2H), 3.52-3.64(m, 1H), 3.22-3.26 (m, 280.01 (M − 1) 1H), 1.70- 2.10 (s, 4H).C₇H₁₁N₃O₇S 50. SO₂ONa H

(DMSO-d₆ D₂O exchange): δ 7.32 (d, 1H), 6.29 (d, 1H), 4.83 (s, 2H),3.95-3.91 (m, 4H) 3.76-3.66 (m, 2H), 2.98-2.88 (dd, 2H), 1.95-1.93 (m,1H), 1.82 (m, 1H), 1.67-1.62 (m, 2H). 374.2 (M − 1) 376.3 (M + 1)(C₁₂H₁₆N₅O₇S•Na) 51. SO₂ONa CH₃ H — 294 for free acid C₈H₁₂N₃O₇S•Na

BIOLOGICAL ACTIVITY

The biological activity of representative compounds according to theinvention against various bacterial strains was investigated. In atypical study, overnight grown bacterial cultures were dilutedappropriately and inoculated on the agar media containing doublingdilutions of the test compounds. Observation for growth or no growth wasperformed after 16-20 hours of incubation at 35±2° C. in ambient air.The overall procedure was performed as per Clinical and LaboratoryStandards Institute (CLSI) recommendations (Clinical and LaboratoryStandards Institute (CLSI), Performance Standards for AntimicrobialSusceptibility Testing, 20th Informational Supplement, M 100-S20, Volume30, No. 1, 2010).

Table 4 describes antibacterial activity of representative compoundsaccording to the invention against various Multi Drug Resistant (MDR)Gram-negative bacterial strains expressing various ESBLs. The activitiesare expressed as MICs (mcg/ml). For comparison, the activity of severalknown antibacterial agents (for example, Ceftazidime, Aztreonam,Imipenem, Ciprofloxacin and Tigecycline) are also included. As can beseen, the representative compounds according to the invention exhibitantibacterial activity against various MDR strains.

TABLE 4 Comparative antibacterial activity of representative compoundsaccording to the invention against various Multi Drug Resistant (MDR)Gram negative strains (expressed as MICs (mcg/ml). Class A ESBL Class CESBL P. aeruginosa E. Coli E. Coli E. Coli E. Coli E. Coli Ps Ps Sr.Compound W 13353 W 13351 W 13352 M 50 H 483 21 32 1. Ceftazidime 3232 >32 >32 >32 >32 >32 2. Aztreonam >32 >32 >32 >32 >32 8 8 3. Imipenem0.25 0.25 0.25 0.5 1 >32 >32 4. Ciprofloxacin >32 0.5 0.12 >32 >32 320.12 5. Tigecyclin 1 1 0.25 0.5 0.5 16 16 6. Example 1 0.5 1 10.5 >32 >32 >32 7. Example 2 1 2 2 1 >32 >32 >32 8. Example 3 8 16 168 >32 >32 >32 9. Example 4 8 8 8 8 >32 >32 >32 10. Example 17 0.5 1 10.5 >32 >32 >32 11. Example 18 0.5 1 1 1 >32 >32 >32 12. Example 19 4 816 8 >32 >32 >32 13. Example 30 4 8 8 4 >32 >32 >32 14. Example 33 44 >32 4 >32 >32 >32 15. Example 35 4 16 8 8 >32 >32 >32

1. A compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof;wherein: R₁ is: (a) SO₃M, (b) SO₂NH₂, (c) PO₃M, (d) CH₂COOM, (e)CF₂COOM, (f) CHFCOOM, or (g) CF₃; M is hydrogen or a cation; R₂ is: (a)hydrogen, (b) (CH₂)_(n)—R₃, or (c) COOR₃, n is 0, 1 or 2; R₃ is: (a)hydrogen, (b) C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from halogen, OR₅, CN, COOR₅,CONR₆R₇, NR₆R₇, NR₅COR₈, NR₅CONR₆R₇, heterocyclyl, heteroaryl,cycloalkyl or aryl, (c) CN, (d) NR₆R₇, (e) CONR₆R₇, (f) NHCONR₆R₇, (g)aryl optionally substituted with one or more substituents independentlyselected from C₁-C₆ alkyl, OR₅, NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl,SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or NHCONR₆R₇, (h) heterocyclyloptionally substituted with one or more substituents independentlyselected from C₁-C₆ alkyl, OR₅, NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl,SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or NHCONR₆R₇, (i) heteroaryl optionallysubstituted with one or more substituents independently selected fromC₁-C₆ alkyl, OR₅, NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl,OSO₂-alkyl, OSO₂-aryl, or NHCONR₆R₇, (j) cycloalkyl optionallysubstituted with one or more substituents independently selected fromC₁-C₆ alkyl, OR₅, NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl,OSO₂-alkyl, OSO₂-aryl, or NHCONR₆R₇, (k) cycloalkyl substituted withC₁-C₆ alkyl wherein C₁-C₆ alkyl is further substituted with one or moresubstituents independently selected from OR₅, NR₆R₇, halogen, CN, orCONR₆R₇, or (l) OR₈; R₄ is: (a) hydrogen, (b) C₁-C₆ alkyl optionallysubstituted with one or more substituents independently selected fromhalogen, OR₅, CN, COOR₅, CONR₆R₇, NR₆R₇, NR₅COR₈, heterocyclyl,heteroaryl, cycloalkyl or aryl, (c) aryl optionally substituted with oneor more substituents independently selected from C₁-C₆ alkyl, OR₅,NR₆R₇, halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl,or NHCONR₆R₇, (d) heterocyclyl optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, OR₅, NR₆R₇,halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, orNHCONR₆R₇, (e) heteroaryl optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, OR₅, NR₆R₇,halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, orNHCONR₆R₇, or (f) cycloalkyl optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, OR₅, NR₆R₇,halogen, CN, CONR₆R₇, SO₂-alkyl, SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, orNHCONR₆R₇; R₅ and R₈ are each independently: (a) hydrogen, or (b) C₁-C₆alkyl optionally substituted with one or more substituents independentlyselected from halogen, CN, CONR₆R₇, NR₆R₇, heterocyclyl, heteroaryl,cycloalkyl or aryl; R₆ and R₇ are each independently: (a) hydrogen, (b)C₁-C₆ alkyl optionally substituted with one or more substituentsindependently selected from halogen, OR₅, CN, COOR₅, CONR₅R₈, NR₅R₈,NR₅COR₈, heterocyclyl, heteroaryl, cycloalkyl or aryl, (c) aryloptionally substituted with one or more substituents independentlyselected from C₁-C₆ alkyl, OR₅, NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl,SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or NHCONR₅R₈, (d) heterocyclyloptionally substituted with one or more substituents independentlyselected from C₁-C₆ alkyl, OR₅, NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl,SO₂-aryl, OSO₂-alkyl, OSO₂-aryl, or NHCONR₅R₈, (e) heteroaryl optionallysubstituted with one or more substituents independently selected fromC₁-C₆ alkyl, OR₅, NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl,OSO₂-alkyl, OSO₂-aryl, or NHCONR₅R₈, (f) cycloalkyl optionallysubstituted with one or more substituents independently selected fromC₁-C₆ alkyl, OR₅, NR₅R₈, halogen, CN, CONR₅R₈, SO₂-alkyl, SO₂-aryl,OSO₂-alkyl, OSO₂-aryl, or NHCONR₅R₈, or (g) R₆ and R₇ are joinedtogether to form a four to seven member ring.
 2. A compound accordingclaim 1, selected from:(2S,5R)-7-oxo-N-[(2S)-pyrrolidin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(2S,4R)-4-hydroxyl-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(2S,4R)-4-cyano-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(5R)-5-cyanopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(SR)-5-cyanopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(2S,4R)-4-trifluoroacetylamino-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(2S)-1-carbamimidoyl-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S ,5R)-7-oxo-N-{1-[(2S)-pyrrolidin-2-yl]ethyloxy}-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-{[(2S)-5-oxopyrrolidin-2-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-N-[(2S)-azetidin-2-ylmethyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-N-[(2R)-azetidin-2-ylmethyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(piperidin-4-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-((3R,S)piperidin-3-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-((2R,S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-((2S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-((2S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-7-oxo-N-{1-[(2S)-piperidin-2-yl]ethyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-N-(azepan-2-ylmethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S)-N-(2,3-dihydro-1H-indol-2-ylmethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S ,5R)-N-{[(2R,S)-1,2,3,4-tetrahydro-quinolin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S ,5R)-N-{[(3S)-1,2,3,4-tetrahydro-isquinolin-3-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(4S)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl]methoxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(4S)-1H-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S)-N-1(4,5-dihydroxy-1,4-dihydropyridin-2-yl)methyloxyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S ,5R)-7-oxo-N-{[(4S)-2-(2-hydroxyphenyl)-4,5-dihydro-1,3-oxazol-4-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-7-oxo-N-{[(4S)-2-((2S)-pyrrolidin-2-yl)-4,5-dihydro-1,3-oxazol-4-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-7-oxo-N-[(3R,S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(3R,5S)-5-cyanopyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(3S,5S)-5-cyanopyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-{[(3R,5S)-5-carbamoylpyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-(azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-methyloxy-7-oxo-N-(piperidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-methyloxy-7-oxo-N-(piperidin-3-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-methyloxy-7-oxo-N-(pyrrolidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-[(2S)-azetidin-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-hydroxy-7-oxo-N-[(2S)-pyrrolidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-hydroxy-7-oxo-N-[(2S)-piperidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-[(2S)-azepan-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-[(2R)-azetidin-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-hydroxy-7-oxo-N-[(2R)-pyrrolidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-hydroxy-7-oxo-N-[(2R)-piperidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;(2S,5R)-N-[(2R)-azepan-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;or a stereoisomer or a pharmaceutically acceptable salt thereof.
 3. Acompound according claim 1, selected from: Sodium salt of (2S,5R)-7-oxo-N-[(2S)-pyrrolidin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of (2S,5R)-7-oxo-N-[(35)-pyrrolidin-3-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of(2S,5R)-N-{[(2S,5R)-4-hydroxyl-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S ,5R)-N-{[(2S,4R)-4-cyanol-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2. 1]octane-2-carboxamide; Sodium salt of (2S,5R)-N-{[(5R)-5-cyanopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2. 1]octane-2-carboxamide; Sodium salt of (2S,5R)-N-{[(SR)-5-cyanopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of (2S ,5R)-N-{[(2S,4R)-4-trifluoroacetylamino-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S ,5R)-N-{[(2S)-1-carbamimidoyl-pyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.21]octane-2-carboxamide; Sodium salt of(2S,5R)-7-oxo-N-{1-[(25)-pyrrolidin-2-yl]ethyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-7-oxo-N-{[(2S)-5-oxopyrrolidin-2-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-[(25)-azetidin-2-ylmethyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-[(2R)-azetidin-2-ylmethyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S,5R)-7-oxo-N-(piperidin-4-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S,5R)-7-oxo-N-((3R,S)-piperidin-3-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-7-oxo-N-((2R,S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S,5R)-7-oxo-N-((2S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S,5R)-7-oxo-N-((2S)piperidin-2-ylmethyloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-7-oxo-N-{1-[(2S)-piperidin-2-yl]ethyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-(azepan-2-ylmethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2. 1]octane-2-carboxamide; Sodium salt of(2S)-N-(2,3-dihydro-1H-indol-2-ylmethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2. 1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-{[(2R,S)-1,2,3,4-tetrahydro-quinolin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S,5R)-N-{[(3S)-1,2,3,4-tetrahydro-isquinolin-3-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of(2S,5R)-N-{[(4S)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl]methoxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-{[(4S)-1H-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of(2S)-N-[(4,5-dihydroxy-1,4-dihydropyridin-2-yl)methyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S,5R)-7-oxo-N-{[(4S)-2-(2-hydroxyphenyl)-4,5-dihydro-1,3-oxazol-4-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of(2S,5R)-7-oxo-N-{[(4S)-2-(2S)-pyrrolidin-2-yl)-4,5-dihydro-1,3-oxazol-4-yl]methyloxy}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of (2S,5R)-7-oxo-N-[(3R,S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S,5R)-N-{[(3R,5R)-5-cyanopyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of (2S,5R)-N-{[(3S,5S)-5-cyanopyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide; Sodium salt of(2S,5R)-N-{[(3R,5R)-5-carbamoylpyrrolidin-3-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of(2S,5R)-N-(azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-methyloxy-7-oxo-N-(piperidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-methyloxy-7-oxo-N-(piperidin-3-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo [3.2.1 ]octane-2-carboxamide; Sodium salt of(2S,5R)-N-methyloxy-7-oxo-N-(pyrrolidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide;(2S,5R)-N-(2-aminoethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidetrifluoroacetic acid salt;(2S,5R)-N-(2-carbamimidamidoethyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carboxamide trifluoroacetic acid salt;(2S,5R)-N-(3-aminopropyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroacetic acid salt;(2S,5R)-N-{[(2S)-2,5-diaminopentyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroaceticacid salt;(2S,5R)-N-{[(2S,4R)-4-aminopyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroacetic acid salt;(2S,5R)-7-oxo-N-[(25)-piperazin-2-ylmethyloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroaceticacid salt;(2S,5R)-N-methyloxy-7-oxo-N-(piperazin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide trifluoroaceticacid salt; Sodium salt of(2S,5R)-N-methoxy-N-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium Salt of (2S,5R)-N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of (2S,5R)-N-[(1-methyl-1H-pyrazol-5-yl)methyloxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-hydroxy-N-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-[(2S)-azetidin-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;Sodium salt of(2S,5R)-N-hydroxy-7-oxo-N-[(2S)-pyrrolidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-hydroxy-7-oxo-N-[(2S)-piperidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-[(25)-azepan-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide; Sodium salt of(2S,5R)-N-[(2R)-azetidin-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-hydroxy-7-oxo-N-[(2R)-pyrrolidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-hydroxy-7-oxo-N-[(2R)-piperidin-2-ylmethyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2. 1]octane-2-carboxamide; Sodium salt of(2S,5R)-N-[(2R)-azepan-2-ylmethyl]-N-hydroxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; or a stereoisomer thereof.
 4. Apharmaceutical composition comprising a compound according to any of theclaims 1 to
 3. 5. A method for preventing or treating bacterialinfection in a subject, said method comprising administering to saidsubject a pharmaceutically effective amount of a compound according toany of the claims 1 to
 3. 6. A method for preventing or treating abacterial infection in a subject, said infection being caused bybacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of a compound according to any of the claims 1 to
 3. 7.A pharmaceutical composition according to claim 4, further comprising atleast one beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof. 8.A pharmaceutical composition according to claim 4 or 7, furthercomprising at least one antibacterial agent or a pharmaceuticallyacceptable derivative thereof.
 9. A method for preventing or treatingbacterial infection in a subject, said method comprising administeringto said subject a pharmaceutically effective amount of a pharmaceuticalcomposition according to claim 4, 7 or
 8. 10. A method for preventing ortreating a bacterial infection in a subject, said infection being causedby bacteria producing one or more beta-lactamase enzymes, wherein themethod comprises administering to said subject a pharmaceuticallyeffective amount of a pharmaceutical composition according to claim 4, 7or
 8. 11. A method for preventing or treating a bacterial infection in asubject, said method comprising administering to said subject apharmaceutically effective amount of: (a) a compound of Formula (I)according to claim 1 or a stereoisomer or a pharmaceutically acceptablesalt thereof, and (b) at least one beta-lactamase inhibitor selectedfrom sulbactam, tazobactam, clavulanic acid, or a pharmaceuticallyacceptable derivative thereof.
 12. A method for preventing or treating abacterial infection in a subject, said infection being caused bybacteria producing one or more beta-lactamase enzymes, said methodcomprising administering to said subject a pharmaceutically effectiveamount of: (a) a compound of Formula (I) according to claim 1 or astereoisomer or a pharmaceutically acceptable salt thereof, and (b) atleast one beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof.13. A method for preventing or treating a bacterial infection in asubject, said method comprising administering to said subject apharmaceutically effective amount of: (a) a compound of Formula (I)according to claim 1 or a stereoisomer or a pharmaceutically acceptablesalt thereof, and (b) at least one antibacterial agent or apharmaceutically acceptable derivative thereof.
 14. A method forpreventing or treating a bacterial infection in a subject, saidinfection being caused by bacteria producing one or more beta-lactamaseenzymes, said method comprising administering to said subject apharmaceutically effective amount of: (a) a compound of Formula (I)according to claim 1 or a stereoisomer or a pharmaceutically acceptablesalt thereof, and (b) at least one antibacterial agent or apharmaceutically acceptable derivative thereof.
 15. A method forpreventing or treating a bacterial infection in a subject, said methodcomprising administering to said subject a pharmaceutically effectiveamount of: (a) a compound of Formula (I) according to claim 1 or astereoisomer or a pharmaceutically acceptable salt thereof; (b) at leastone beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof,and (c) at least one antibacterial agent or a pharmaceuticallyacceptable derivative thereof.
 16. A method for preventing or treating abacterial infection in a subject, said infection being caused bybacteria producing one or more beta-lactamase enzymes, said methodcomprising administering to said subject a pharmaceutically effectiveamount of: (a) a compound of Formula (I) according to claim 1 or astereoisomer or a pharmaceutically acceptable salt thereof, (b) at leastone beta-lactamase inhibitor selected from sulbactam, tazobactam,clavulanic acid, or a pharmaceutically acceptable derivative thereof,and (c) at least one antibacterial agent or a pharmaceuticallyacceptable derivative thereof.
 17. A method for increasing antibacterialeffectiveness of a antibacterial agent in a subject, said methodcomprising co-administering said antibacterial agent or apharmaceutically acceptable derivative thereof with a pharmaceuticallyeffective amount of a compound of Formula (I) according to claim 1, or astereoisomer or a pharmaceutically acceptable salt thereof.
 18. Apharmaceutical composition according to claim 8 or a method according toany of the claim 9, 10, 13, 14, 15, 16 or 17, wherein the antibacterialagent is selected from a group consisting of aminoglycosides,ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides,lipopeptides, macrolides, monobactams, nitrofurans, penicillins,polypeptides, quinolones, sulfonamides, tetracyclines, or oxazolidinoneantibacterial agents.
 19. A pharmaceutical composition according toclaim 8 or a method according to any of the claim 9, 10, 13, 14, 15, 16or 17, wherein the antibacterial agent is a beta-lactam antibacterialagent.
 20. A pharmaceutical composition according to claim 8 or a methodaccording to any of the claim 9, 10, 13, 14, 15, 16 or 17, wherein saidantibacterial agent is selected from a group consisting of penicillins,penems, carbapenems, cephalosporins, and monobactams.
 21. Apharmaceutical composition according to claim 8 or a method according toany of the claim 9, 10, 13, 14, 15, 16 or 17, wherein the antibacterialagent is a cephalosporin antibiotic selected from a group consisting ofcephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole,cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile,cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime,cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime,cefpirome, ceftazidime, ceifriaxone, cefpiramide, cefbuperazone,cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole,cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil,cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapenepivoxil or cefditoren pivoxil, cefuroxime, cefuroxime axetil,loracarbacef, ceftaroline and latamoxef.
 22. A pharmaceuticalcomposition according to claim 8 or a method according to any of theclaim 9, 10, 13, 14, 15, 16 or 17, wherein the antibacterial agent isselected from a group consisting of ceftazidime, cefepime, cefpirome,piperacillin doripenem, meropenem, imipenem, ceftaroline andceftolozane.
 23. A pharmaceutical composition according to claim 8 or amethod according to any of the claim 9, 10, 13, 14, 15, 16 or 17,wherein the antibacterial agent is selected from a group consisting ofaminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins,lincosamides, lipopeptides, macrolides, monobactams, nitrofurans,penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, oroxazolidinone antibacterial agents.